The present invention relates to a pharmaceutical dosage form comprising an antihyperglycemic drug, in combination with a second drug. More specifically, the present invention relates to an oral dosage form comprising a biguanide, e.g., metformin or buformin or a pharmaceutically acceptable salt thereof e.g., metformin hydrochloride or the metformin salts described in U.S. Pat. Nos. 3,957,853 and 4,080,472, which are incorporated herein by reference in combination with an angiotensin antagonist as described in U.S. Pat. Nos. 5,196,444; 5,534,534; 5,703,110; and 5,705,517 also incorporated herein by reference.
Many techniques have been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance.
For example, extended release tablets have been described which have an osmotically active drug core surrounded by a semi-permeable membrane. These tablets function by allowing the aqueous components of a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so the resultant drug solution can be released through a passageway in the coating membrane. Alternatively, if the active ingredient is insoluble in the permeating fluid, it can be pushed through the passageway by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet systems can be found in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and 4,783,337. U.S. Pat. No. 3,952,741 teaches an osmotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has developed within the membrane to burst or rupture the membrane at a weak portion of the membrane.
The basic osmotic device described in the above cited patents have been refined over time in an effort to provide greater control of the release of the active ingredient. For example, U.S. Pat. Nos. 4,777,049 and 4,851,229 describe osmotic dosage forms comprising a semipermeable wall surrounding a core. The core contains an active ingredient and a modulating agent wherein the modulating agent causes the active ingredient to be released through a passageway in the semipermeable membrane in a pulsed manner. Further refinements have included modifications to the semipermeable membrane surrounding the active core such as varying the proportions of the components that form the membrane, e.g. U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625, or increasing the number of coatings surrounding the active core, e.g., U.S. Pat. Nos. 5,650,170 and 4,892,739.
Certain controlled or sustained release formulations that employ antihyperglycemic drugs such as metformin hydrochloride have been limited to the use of an expanding or gelling agent to control the release of the drug from the dosage form. This limited research is exemplified by the teachings of WO 96/08243 and by the product insert for GLUCOPHAGE™ XR, which is a controlled release metformin HCl product commercially available from Bristol-Myers Squibb Co.
Angiotensin antagonists have been described in U.S. Pat. Nos. 5,196,444; 5,534,534 and 5,705,517. The therapeutic value of these compounds in combination therapy has further been described in published PCT application WO 0215933. However, none of these patents, or the publication describe a dosage form having the advantages of the subject invention.
Angiotensin antagonists are compounds functioning to control the renin-angiotensin system as well as being clinically useful for the treatment of circulatory diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, etc. These compounds are required to have potent angiotensin II receptor antagonistic activity and to exert strong oral and long-lasting angiotensin II antagonist action. Several 2-substituted benzimidazole derivatives possessing highly angiotensin II receptor antagonistic activity as well as exerting strong oral and long-lasting angiotensin II antagonistic and anti-hypertensive action have been developed. These compounds are potent angiotensin II antagonists that are of value in the treatment of circulatory system diseases such as hypertensive diseases, heart diseases, strokes, nephritis, etc.
Also known in the art is WO 99/47125 and U.S. Pat. No. 6,099,862 that disclose a metformin osmotic tablet coated with an immediate release coating containing an antihyperglycemic or a hypoglycemic drug.
Although the prior art teaches pharmaceutical dosage formulations that contain both an antihyperglycemic compound and an angiotensin antagonist, the present invention provides numerous benefits over the prior art teachings as will be described below.